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近日，WHO在其技術報告TRS1060中發布了新的《藥用輔料GMP》-2025，現將中英文翻譯分享給大家：
Appendix 2
附錄 2
List of examples of high - risk excipients and contaminants
高風險輔料和污染物示例列表
1.Introduction
1.引言
The purpose of this appendix is to provide a list of examples of high - risk excipients and contaminants, where manufacturers of such excipients (as well as manufacturers of finished pharmaceutical products (FPPs) containing such excipients) are alerted to implement control measures to ensure the safety, purity and quality of these excipients and FPPs.
本附錄的目的是提供一份高風險輔料和污染物的示例列表,提醒輔料制造商(以及含有此類輔料的最終藥品成品(FPPs)的制造商)采取控制措施,以確保此類輔料和FPPs的安全性、純度和質量。
Manufacturers should perform risk assessments to identify and assess the level of risk and potential harm associated with the production, control, storage, distribution and use of excipients, and implement appropriate levels of control to mitigate the risks and harm.
制造商應進行風險評估,以識別和評估生產、控制、儲存、分發和使用輔料相關的風險和潛在危害,并采取適當的控制措施來減輕這些風險和危害。
The list is not exhaustive, but provides examples of high - risk excipients and contaminants that require appropriate levels of control to mitigate the risks and harm. The list will be updated at intervals.
該列表并非詳盡無遺,但提供了需要采取適當控制措施以減輕風險和危害的高風險輔料和污染物的示例。該列表將定期更新。
Excipients may be at high risk due to:
輔料可能因以下原因而處于高風險狀態:
the nature of the material;
材料的性質;
contamination with toxic substances as a result of (for example) the production process, other chemicals, solvents or carry - over from residue on equipment;
由于生產過程、其他化學品、溶劑或設備殘留物的殘留等原因導致的有毒物質污染
having been mixed with other industrial products that are toxic;
與其他有毒工業產品混合;
unintentional or intentional contamination by suppliers, packers, packaging material or other means.
供應商、包裝商、包裝材料或其他手段造成的無意或故意污染。
Additional considerations and controls may have to be implemented.
還需考慮的控制措施可能需要額外實施。
Manufacturers, suppliers and distributors of excipients should:
輔料制造商、供應商和分銷商應:
perform risk assessment to determine the potential risks and harms in using raw materials in the production of excipients and implement appropriate controls to mitigate such risks and harms;
進行風險評估,以確定使用生產輔料所需原材料的潛在風險和危害，并采取適當的控制措施來減輕這些風險和危害；
purchase materials suitable for use from reliable suppliers;
從可靠的供應商處采購適合使用的材料;
use solvents of appropriate quality;
使用適當質量的溶劑;
ensure that appropriate sampling and testing is done to determine whether the excipient contains any unwanted contaminant;
確保進行適當的取樣和檢測,以確定輔料是否含有任何不必要的污染物；
consider comprehensive quality control testing throughout the manufacturing and distribution chain;
考慮在整個生產和分銷鏈中進行全面的質量控制檢測。
ensure excipients are manufactured in line with good manufacturing practices;
確保輔料的生產符合良好生產規范
keep accurate, complete and appropriate records of distribution of materials and their testing;
保持準確、完整且適當的材料分發及其檢驗記錄;
check for signs of falsification and physical condition of materials across the manufacturing, storage and distribution chain;
在生產、存儲和分發鏈中檢查偽造跡象和材料的物理狀態;
ensure full batch traceability from manufacture through the supply chain to customers;
確保從生產到供應鏈最終客戶的整個批次可追溯性;
provide assurance of excipient quality and purity, including through certificates of analyses based on appropriate testing results as per specification.
提供輔料質量與純度的保證,包括基于適當測試結果的分析證書。
Manufacturers (and, where appropriate, suppliers and distributors) of FPPs containing high risk excipients should:
含有高風險輔料的FPP(成品藥品)制造商(以及在適當情況下,輔料供應商和分發商)應:
perform risk assessment to determine the potential risks and harms in using excipients in the production of an FPP and implement appropriate controls to mitigate such risks and harms;
進行風險評估,以確定使用輔料在生產FPP過程中潛在的風險和危害,并實施適當的控制措施以減輕這些風險和危害;
purchase pharmaceutical grade excipients from qualified suppliers;
從合格供應商處購買藥品級輔料;
conduct appropriate testing upon receipt of supplies and before use in manufacture of FPPs;
在接收輔料并用于FPP生產之前,進行適當的檢測;
provide assurance of excipient quality, including through certificates of analyses based on appropriate testing results as per registered specifications;
提供輔料質量的保證,包括基于適當測試結果的分析證書,符合注冊規格;
keep accurate, complete and appropriate records of purchase of materials and their testing;
記錄購買材料及其檢測的準確、完整和適當的記錄;
check for signs of substandard material, falsification and poor physical condition of materials;
檢查材料是否有不合格的跡象、偽造和不良物理狀態;
perform robust inspection of incoming goods, quality control testing and material release according to applicable monographs or equivalent validated and appropriate internal methods;
根據適用的藥典或等效的驗證和適當的內部方法,對到貨商品進行嚴格的檢查、質量控制檢測和材料放行;
ensure full traceability of the supply chain back to the original excipient manufacturer;
確保供應鏈的完全可追溯性,追溯到原始輔料制造商;
perform on-site audit of the manufacturing site of the excipient, where appropriate;
在適當情況下,對輔料制造商的生產現場進行現場審核;
keep accurate, complete and appropriate records relating to the medicines and their distribution and sale.
記錄與藥品及其分銷和銷售相關的準確、完整和適當的記錄。
For more guidance on risk assessment, see Appendix 1.
有關風險評估的更多指導,請參見附錄1。
2.List of excipients
2.（高風險）輔料列表
Note: Identified excipients will be added to the list from time to time.
注：已識別的輔料將不時添加到列表中。
Ethanol (ethyl alcohol)
乙醇（酒精）
2-Propanol (isopropyl alcohol)
2-丙醇（異丙醇）
Glycerol
甘油
Hydrogenated starch hydrolysates
氫化淀粉水解物
Maltitol solution
莫爾糖漿溶液
Propylene glycol
丙二醇
Sorbitol solution
山梨醇溶液
2.1 Ethanol (ethyl alcohol) and 2-propanol (isopropyl alcohol)
2.1 乙醇（酒精）和2-丙醇(異丙醇)
Introduction and use
簡介與用途
Ethanol is a clear, colourless, volatile organic compound with a characteristic odour. It is highly flammable.
乙醇是一種清澈、無色、易揮發的有機化合物,具有特有的氣味。它極易燃燒。
Toxicity
毒性
Ethanol is sometimes used in pharmaceutical products such as oral liquid medicine, and other products such as mouthwashes and sanitizer products. Overdose may result in mental confusion, vomiting, seizure, slow - ing of heart rate and breathing. It may also lead to brain damage and death.
乙醇有時被用作制藥產品中的口服液劑,以及其他產品如漱口水和消毒劑產品中的成分。過量攝入可能導致意識混亂、嘔吐、抽搐、心率和呼吸減緩。還可能導致腦損傷甚至死亡。
Risks and controls
風險與控制
Besides the toxic effects of ethanol, another risk is that it may be contaminated with, or substituted with, methanol.
除了乙醇的毒性作用外,另一個風險是乙醇或異丙醇可能被甲醇污染或替代。
Controls should therefore include supply chain management with appropriate tests to identify the solvent and, in particular, the amount of methanol present in ethanol and isopropyl alcohol data. Reliance solely on a certificate of analysis may not be appropriate.
因此,控制措施應包括供應鏈管理,并進行適當的檢測以識別溶劑,特別是乙醇和異丙醇中甲醇的含量。僅依賴分析證書可能不夠適當。
Recommendations
建議
Repackers of ethanol and isopropyl alcohol to be supplied to manufacturers of FPPs should ensure the appropriate quality of ethanol and isopropyl alcohol.
建議向FPP制造商供應乙醇和異丙醇的重新包裝商應確保乙醇和異丙醇的質量符合要求。
Manufacturers of FPPs should ensure that the manufacturers of ethanol and isopropyl alcohol in the supply chain are appropriately qualified.
FPP制造商應確保供應鏈中乙醇和異丙醇的制造商具備相應的資質。
Quality control should consist of sampling and testing of every container, in consignment, according to the specification in a monograph of a pharmacopoeia, which includes an identification test and a limit test for methanol.
質量控制應包括根據藥典中相應藥典法典的規定對每批貨物中的每個容器進行采樣和檢測,其中包括識別測試和甲醇限量測試。
The FPP analytical procedure should be appropriate and ensure that when testing for ethanol or isopropyl alcohol (assay), the method also distinguishes between the active ingredient and ethanol.
FPP 分析程序應當適當,并確保在檢測乙醇或異丙醇(含量測定)時,該方法還能區分有效成分與乙醇。
2.2 Glycerol
2.2 甘油
Introduction and use
簡介與應用
Glycerol is a naturally occurring odourless alcohol. It is used as a solvent, sweetening agent and medicine.
甘油是一種天然存在的無味醇類化合物。它用作溶劑、甜味劑和藥物。
Toxicity
毒性
Documented side - effects may include nausea, gastrointestinal discomfort, dizziness and headache.
毒性已記錄的副作用可能包括惡心、胃腸道不適、頭暈和頭痛。
Risks and controls
風險與控制
Glycerol is considered a high - risk excipient, as it is often contaminated with toxic substances such as DEG. Controls should be applied to ensure that glycerol is of the required purity, and is not contaminated with a contaminant (such as DEG) that can cause death when ingested.
甘油被視為高風險輔料,因為其常被有毒物質如二甘醇(DEG)污染。應采取措施確保甘油達到所需的純度標準,并且不含可能在攝入時導致死亡的污染物(如DEG)。
Agents, suppliers and repackers should test glycerol for contamination prior to its distribution, when the intended use is in the production of pharmaceutical products. As glycerol may be handled by several importers, exporters and suppliers before reaching an end destination, manufacturers of FPPs must adequately test glycerol for its purity and the presence of contaminants such as DEG. Appropriate, suitably validated analytical methods should be used. As infrared spectroscopy tests may not be sufficient to detect DEG contamination in glycerol syrup, a gas chromatography method capable of separating and detecting glycerol, EG and DEG can be used to determine that glycerol is free of these contaminants (see also the section on DEG).
在甘油用于制藥產品的生產之前,其分銷商、供應商和分裝商應對其進行污染檢測。由于甘油可能在到達最終目的地之前經過多個進口商、出口商和供應商的處理,生產FPP(仿制藥)的制造商必須對其純度和是否存在DEG等污染物進行充分檢測。應使用適當的、經過驗證的分析方法。由于紅外光譜測試可能不足以檢測甘油糖漿中的DEG污染,可以使用能夠分離和檢測甘油、乙二醇(EG)和二甘醇(DEG)的氣相色譜法來確定甘油是否不含這些污染物(參見DEG部分)。
2.3 Hydrogenated starch hydrolysates (HSHs)
2.3 氫化淀粉水解物（HSHs）
Introduction and use
簡介與應用
Hydrogenated starch hydrolysates (HSHs) are common ingredients used in the manufacture of over - the - counter allergy, cough and cold medicines. HSHs are mixtures of sorbitol, maltitol and higher - order sugar alcohols. They are food ingredients because of their sweetness and useful functional properties. Polyglycitol syrup is a mixture of several sugar alcohols (a type of sugar substitute). HSHs are similar to sorbitol.
氫化淀粉水解物(HSHs)是常用于非處方抗過敏、止咳和感冒藥物制造的常見成分。HSHs 是山梨醇、麥芽糖醇及其高聚糖醇的混合物。由于其甜味和實用的功能特性,它們被視為食品添加劑。聚甘油醇糖漿是由幾種糖醇(一種糖替代品)組成的混合物。HSHs 與山梨醇相似。
HSHs are often used both as a sweetener and as a humectant (moisture - retaining ingredient). As a crystallization modifier, they can prevent syrups from forming crystals of sugar. They are used to add bulk, body, texture and viscosity to mixtures, and can protect against damage from freezing and drying.
HSHs 通常既用作甜味劑,又用作保濕劑(保持濕潤的成分)。作為結晶修飾劑,它們可以防止糖形成結晶。它們被用于增加混合物的體積、質地和粘度,并能防止因凍結和干燥造成的損害。
Toxicity
毒性
HSHs could be contaminated with diethylene glycol or ethylene glycol (DEG or EG) (see section on DEG and EG toxicity).
HSHs 可能會受到二甘醇或乙二醇(DEG 或EG)的污染(見二甘醇和乙二醇毒性部分)。
Risks and controls
風險與控制措施
HSHs are considered high-risk excipients, as they are often contaminated with hazardous substances such as DEG. Controls should be applied to ensure that HSHs are of the required purity, and are not contaminated with a contaminant (such as DEG) that can cause death when ingested.
HSHs 被視為高風險的輔料,因為它們經常受到諸如 DEG 等有害物質的污染。應采取措施確保 HSHs 達到所需的純度標準,并且不含如 DEG 等可導致攝入后死亡的污染物。
Agents, suppliers and repackers should test HSH for contamination prior to its distribution, when the intended use is in the production of pharmaceutical products. As HSH may be handled by several importers, exporters and suppliers before reaching an end destination, manufacturers of FPPs must adequately test HSH for its purity and the presence of contaminants such as DEG. Appropriate, suitably validated analytical methods should be used (see section on DEG).
在HSHs 用于制藥產品生產之前,其分銷前的代理商、供應商和重新包裝商應對其進行污染檢測。由于 HSHs 可能會經過多個進口商、出口商和供應商之手才能到達最終目的地,因此 FPPs 的制造商必須充分檢測 HSHs 的純度及其是否含有如DEG 等污染物。應采用合適的、經過驗證的分析方法(見二甘醇部分)。
2.4 Maltitol solution
2.4 甘露糖醇溶液
Introduction and use
簡介與應用
Maltitol is a sugar alcohol and also considered a carbohydrate. Sugar alcohols are found naturally in some fruits and vegetables. They are typically manufactured rather than being used in their natural form.
甘露糖醇是一種糖醇,也可被視為一種碳水化合物。糖醇在某些水果和蔬菜中自然存在。通常,它們是通過制造而不是以天然形式使用。
Toxicity
毒性
Maltitol solution can be contaminated with DEG or EG (see sections on DEG and EG toxicity).
甘露糖醇溶液可能受到二甘醇(DEG)或乙二醇(EG)的污染(參見DEG和EG的毒性部分)。
Risks and controls
風險與控制
Maltitol solution is considered a high-risk excipient, as it is often contaminated with hazardous substances such as DEG. Controls should be applied to ensure that maltitol solution is of the required purity, and is not contaminated with a contaminant (such as DEG) that can cause death when ingested.
蔗糖醇溶液被視為高風險的賦形劑,因為它經常受到如DEG等有害物質的污染。應采取措施確保蔗糖醇溶液達到所需的純度標準,并且不含可能在攝入時導致死亡的污染物(如DEG)。
Repackers should test maltitol solution for contamination prior to its distribution, when the intended use is in the production of pharmaceutical products.
在制藥產品生產中使用前,再包裝商應測試甘露糖醇溶液是否存在污染。
Appropriate, suitably validated analytical methods should be used (see also the section on DEG).
應使用適當的、經過驗證的分析方法進行檢測(參見DEG部分)。
2.5 Propylene glycol
2.5 丙二醇
Introduction and use
簡介與用途
Propylene glycol, a diol alcohol, is an organic compound. It is a tasteless, viscous, colourless, nearly odourless liquid. It possesses a faintly sweet taste.
丙二醇是一種二醇醇類有機化合物。它是一種無味、粘稠、無色、幾乎無味的液體。它具有輕微的甜味。
Propylene glycol is produced for the production of polymers and various other industrial applications.
丙二醇主要用于聚合物的生產以及各種其他工業應用。
It is used in food, cosmetics and pharmaceuticals.
它被用于食品、化妝品和制藥領域。
Toxicity
毒性
Propylene glycol should be of an appropriate grade when used in pharmaceutical products. It can be toxic to the kidneys and liver, especially in children, when given in high doses.
在制藥產品中使用丙二醇時,其純度應符合相應標準。高劑量下,它可能對腎臟和肝臟有毒性,尤其是在兒童身上。
Risks and controls
風險與控制
Although propylene glycol is relatively safe for use in pharmaceutical products, it has sometimes been contaminated with toxic substances such as DEG and EG. Controls should be in place to prevent such contamination.
盡管丙二醇在制藥產品中的使用相對安全,但有時會被二甘醇(DEG)和乙二醇(EG)等有毒物質污染。應采取措施防止此類污染。
Controls should be in place to detect contaminants (such as DEG and EG) in propylene glycol.
應建立檢測措施以檢測丙二醇中的污染物(如二甘醇和乙二醇)。
Note: See also pharmacopoeia for the determination of ethylene glycol, diethylene glycol, and triethylene glycol in polyethylene glycol.
注意事項:參見藥典中關于聚乙二醇中乙二醇、二乙二醇和三乙二醇的測定方法。
2.6 Sorbitol solution
2.6 山梨醇溶液
Introduction and use
簡介與應用
Sorbitol is a sugar alcohol with a sweet taste. It is used as a natural sweetener, and is sometimes presented in soft gel capsules. It is also used in the manufacture of allergy, cold and cough medication.
山梨醇是一種具有甜味的糖醇,常被用作天然甜味劑,并有時以軟膠囊形式呈現。此外,它還用于過敏、感冒和咳嗽藥物的制造。
Toxicity
毒性
Sorbitol solution is not toxic.
山梨醇溶液無毒。
Risks and controls
風險與控制
Although sorbitol solution is relatively safe for use in pharmaceutical products, it has sometimes been contaminated with hazardous substances. Controls should be in place to prevent such contamination, and controls should be in place to detect contaminants (such as DEG and EG).
盡管山梨醇溶液在制藥產品中的使用相對安全,但有時會受到有害物質的污染。應采取措施防止此類污染,并應建立檢測措施以發現污染物(如二甘醇和乙二醇)。
2.7 Other excipients that may be contaminated by DEG and EG
2.7 其他可能被二甘醇（DEG）和乙二醇（EG）污染的輔料
Other excipients that may be contaminated by DEG and EG include:
其他可能被二甘醇(DEG)和乙二醇(EG)污染的輔料包括:
Polyethylene glycol (macrogol)?
聚乙二醇（聚環氧乙烷）?
Diethylene glycol stearates
二甘醇硬脂酸酯
Polyethylene glycol monomethyl ether 350/550 (molecular weight below 600 only)
聚乙二醇單甲醚 350/550（僅分子量低于 600 的）
Polyoxyl 35 castor oil
聚氧乙烯 35 蓖麻油
Polysorbate 20/40/60/80
聚山梨酯 20/40/60/80
Polyoxyl 15 hydroxystearate
聚氧乙烯 15 羥基硬脂酸酯
Polyoxyl 20 cetostearyl ether
聚氧乙烯 20 鯨蠟硬脂基醚
Polyoxyl 18 stearate
聚氧乙烯 18 硬脂酸酯
Octoxynol 9
辛苯昔醇 9
Nonoxynol 9.
壬苯醇醚 9
DEG and EG can be present as contaminants or impurities in some of the excipients listed above. The seller of an excipient should ensure adequate controls and, where appropriate, tests to assure acceptable quality and purity of the excipient.
DEG和EG可能作為雜質存在于上述列出的一些輔料中。輔料的供應商應確保采取適當的控制措施,并在適當的情況下進行測試,以確保輔料的質量和純度符合要求。
3.List of contaminants
3.污染物清單
The subsections below consider the following contaminants:
污染物列表以下子節考慮了以下污染物:
Diethylene glycol (DEG)
二甘醇（DEG）
Ethylene glycol (EG)
乙二醇（EG）
Nitrosamines.
亞硝胺
3.1 Diethylene glycol (DEG)
3.1 二甘醇（DEG）
Introduction and use
簡介與用途
DEG is a contaminant, and is not an excipient. It is however sometimes present in some excipients.
DEG 是一種污染物,而不是賦形劑。然而,在某些賦形劑中有時會檢測到 DEG 的存在。
DEG is a colourless chemical for use in industrial applications only, such as industrial solvents, coolants, brake fluids and antifreeze agents. It is not approved for use in food and pharmaceutical applications.
DEG 是一種僅用于工業應用的無色化學物質,如工業溶劑、冷卻劑、剎車液和防凍劑。它未被批準用于食品和制藥應用。
Because of its solubility, some manufacturers have inappropriately used it in pharmaceutical products such as cough syrups and acetaminophen syrup in place of glycerol. In some cases, instead of using safer, more expensive diluents such as pharmaceutical grade glycerol, manufacturers have used alternative diluents that have been contaminated with DEG.
由于其溶解性,一些制造商不當將其用于制藥產品,如咳嗽糖漿和對乙酰氨基酚糖漿,替代甘油。在某些情況下,制造商沒有使用更安全但成本更高的稀釋劑,如藥用級甘油,而是使用了可能被二甘醇(DEG)污染的替代稀釋劑。
Toxicity
毒性
Due to its toxicity DEG is potentially fatal, especially for young children, for example when it is inadvertently or deliberately incorporated as a component of a medicinal syrup or other liquid pharmaceutical formulation. The effects may include severe kidney damage, potentially resulting in death.
由于其毒性,DEG有可能致命,尤其是對于兒童,例如當其意外或故意作為藥物糖漿或其他液體制劑的成分時。其影響可能包括嚴重的腎損傷,甚至可能導致死亡。
The possibility of some DEG contamination of raw materials during the raw ingredient and final product manufacturing process cannot be excluded. In these particular situations, DEG may simply be a minor impurity created during the manufacturing process of chemicals used to formulate drugs and consumer products.
在原料和最終產品制造過程中,DEG污染原材料的可能性不能排除。在這種特定情況下,DEG可能是化學藥物和消費品配方過程中產生的微量雜質。
The first known case of DEG poisoning with medicine occurred in the United States in 1937, when DEG was used in an elixir of an antibiotic, sulfanilamide. Other DEG - related poisonings have also been reported in Argentina, Bangladesh, China, Haiti, India, Nigeria and Panama. Some of these countries have a history of multiple events, even though incidents are preventable with the right quality controls and risk assessments.
DEG中毒的第一例發生在1937年的美國,當時DEG被用于一種抗生素合劑——磺胺酏劑。此后,DEG相關的中毒事件也在阿根廷、孟加拉國、中國、海地、印度、尼日利亞和巴拿馬等地報告過。盡管這些事件是可預防的,但一些國家多次發生此類事件,因為正確的質量控制和風險評估可以預防此類事件。
Risks and controls
風險與控制
DEG can enter the supply chain in several ways, for example through mislabelled products, human error, or unintentional contamination or intentional adulteration by manufacturers, repackers or suppliers.
DEG可以通過多種方式進入供應鏈,例如通過標簽錯誤的產品、人為錯誤、無意污染或制造商、分裝商或供應商有意摻假。
Appropriate controls, including supplier approval of raw materials and excipients and sampling and testing of raw materials and excipients, can be used to detect the presence of DEG. Appropriate analytical procedures should be used when testing for the presence of DEG.
適當的控制措施,包括原材料和輔料的供應商審批、原材料和輔料的取樣和檢測,可以用于檢測DEG的存在。檢測DEG時應使用適當的分析程序。
End - product testing alone is not appropriate, given the complex production, control and supply chain of excipients.
僅對最終產品進行檢測是不合適的,因為輔料的復雜生產、控制和供應鏈過程。
Analytical methodology, such as gas chromatography with flame ionization detection (GC/FID) or high - performance liquid chromatography with refractive index detection (HPLC/RID), may be considered.
氣相色譜-火焰離子化檢測(GC/FID)或高效液相色譜-折射率檢測(HPLC/RID)等分析方法可能被考慮使用。
DEG should comply with the requirements of an official pharmacopeia. Otherwise, in - house methods should be suitably validated for their intended use and should be appropriately validated. The satisfactory application of such methods requires the necessary analyst expertise, suitable equipment and validated procedures.
DEG應符合官方藥典的要求。否則,內部方法應適合其預期用途,并應適當驗證。此類方法的有效應用需要必要的分析員專業知識、合適的設備和驗證的程序。
3.2 Ethylene glycol (EG)
3.2 乙二醇（EG）
Introduction and use
簡介與用途
EG is a contaminant, and is not an excipient. It is however sometimes present in some excipients.
EG 是一種污染物,而不是輔料。然而,在某些輔料中可能會檢測到 EG。
EG is a colourless, odourless, sweet - tasting chemical. It is mainly used in antifreeze, coolants, detergents, paints, lacquers, adhesives and cosmetics.
EG 是一種無色、無味、甜味的化學物質。它主要用于防凍劑、冷卻劑、洗滌劑、油漆、清漆、粘合劑和化妝品。
EG is poisonous if swallowed. It is a central nervous system depressant that produces acute effects similar to those of ethanol. Ingestion can cause serious or fatal toxicity.
口服 EG 是有毒的。它是一種中樞神經系統抑制劑,其急性效應與乙醇相似。攝入 EG 可能導致嚴重甚至致命的毒性。
Toxicity
毒性
Symptoms after ingestion may include nausea, vomiting, convulsions, stupor and coma. An overdose of EG can damage the brain, lungs, liver and kidneys. The poisoning causes metabolic acidosis, shock, organ failure and death.
攝入后可能出現的癥狀包括惡心、嘔吐、抽搐、昏睡和昏迷。EG 過量可損害大腦、肺、肝和腎。中毒可導致代謝性酸中毒、休克、器官衰竭和死亡。
Risks and controls
風險與控制
Appropriate controls, including supplier approval of raw materials and excipients and sampling and testing of raw materials and excipients, can be used to detect the presence of EG. Appropriate analytical procedures should be used when testing for the presence of EG.
適當的控制措施,包括供應商對原材料和輔料的批準、原材料和輔料的取樣與檢測,可以用于檢測 EG 的存在。在檢測 EG 存在時,應使用適當的分析方法。
End - product testing alone is not appropriate, given the complex production, control and supply chain of excipients.
僅通過最終產品的檢測是不合適的,考慮到輔料的復雜生產、控制和供應鏈。
3.3 Nitrosamines
3.3 亞硝胺
Note: See WHO good practice considerations for the prevention and control of nitrosamines in pharmaceutical products (Annex 2, Technical Report Series No. 1060, 2025).
注意:有關制藥產品中亞硝胺預防和控制的良好實踐考慮,請參見世界衛生組織的技術報告系列第1060號,2025年版(附件2)。
Introduction and use
引言與使用
Nitrosamines are a contaminant, and not an excipient. Nitrosamines are formed by a reaction between nitrites and vulnerable (especially secondary) amines. Nitrosamines and their precursors can be found in various foods and consumer products, and in some pharmaceutical products.
亞硝胺是一種污染物,而非輔料。亞硝胺是由亞硝酸鹽與敏感胺(尤其是二級胺)反應生成的。亞硝胺及其前體可在多種食品、消費品以及某些制藥產品中被發現。
Toxicity
毒性
Nitrosamines can be carcinogenic when ingested at certain doses over a period of time.
亞硝胺在特定劑量下長期攝入時具有致癌性。
Risks and controls
風險與控制
The presence of nitrosamines in pharmaceutical products can present a carcinogenic risk. Manufacturers of excipients and FPPs should perform a risk assessment to determine whether there is a possibility of nitrosamine formation during the production of an excipient or during the production of an FPP, for example as a result of a chemical reaction between nitrites and vulnerable (especially secondary) amines.
硝胺類物質在制藥產品中的存在會帶來致癌風險。輔料和藥用輔料產品的制造商應進行風險評估,以確定在輔料或藥用輔料產品生產過程中是否有可能形成硝胺,例如由于亞硝酸鹽與敏感(尤其是二級)胺發生化學反應所致。
4.Summary and recommendations
4.總結與建議
Excipients for use in pharmaceutical products should be produced, controlled, stored and distributed in compliance with the relevant WHO good practice guidelines.
制藥產品中使用的輔料應按照相關世衛組織良好實踐指南進行生產、控制、存儲和分發。
Excipients for pharmaceutical use should be of appropriate quality and purity.
制藥用輔料應具備適當的品質和純度。
Manufacturers should identify excipients that may be at high risk of being contaminated with a hazardous substance.
生產商應識別出可能高度風險被有害物質污染的輔料。
Due to the high risk of some excipients being contaminated with hazardous substances, a risk assessment should be performed and controls implemented to ensure the excipients are of the required purity and for their intended use and, if contaminants such as DEG and EG are present, they are not above the limiting level.
鑒于某些輔料高度風險被有害物質污染,應進行風險評估并實施控制措施,以確保輔料符合其預期用途所需的純度標準,若存在如二甘醇(DEG)和乙二醇(EG)等污染物,則其含量不得超過限制水平。
This document lists examples of excipients that may be at high risk of being contaminated.
本文件列出了可能高度風險被污染的輔料示例。
All high-risk excipients identified should be appropriately controlled.
所有識別出的高風險輔料均應實施適當的控制措施。
Controls may include the following.
控制措施可能包括以下內容:
Production, control, storage, repackaging and distribution should be in compliance with WHO good practices.
生產、控制、存儲、重新包裝和分發應符合WHO的良好實踐標準。
Specifications with authoritative excipients should be equal to or better than those in the recognized pharmacopoeia.
對輔料的規格應不低于認可藥典中的標準。
Specifications should include limits for impurities.
規格應包含雜質的限度。
Suppliers, distributors, repackers and agents supplying excipients for use in pharmaceutical products should implement appropriate controls to prevent any contamination of these excipients.
為制藥產品提供輔料的供應商、分銷商、重新包裝商和代理應實施適當的控制措施,以防止這些輔料被污染。
The original certificate of analysis from the excipient manufacturer should be available for every batch of the excipient.¹?
每批輔料應提供可追溯制造商的原始分析證書。
Repackers of excipients for use in pharmaceutical products should comply with WHO good manufacturing practices and good trade and distribution practices.
制藥輔料的重新包裝商應遵守世界衛生組織(WHO)的優良制造規范和優良貿易與分銷規范。
Manufacturers of intermediate or finished pharmaceutical products should:
制造中間體或成品藥品的生產商應:
ensure that all personnel are aware of the risks associated with the contamination of excipients, and are trained in good practices;
確保所有人員了解輔料污染的風險,并接受優良操作規范的培訓;
purchase these excipients from approved suppliers, through a known supply chain (including repacker and distributor);
從已批準的供應商處通過已知的供應鏈(包括重新包裝商和分銷商)采購這些輔料;
sample every container of each batch or lot of the listed excipients, and perform an identity and limit test for contaminants such as methanol or DEG and EG. Each sample should meet the predefined specification, including the safety limit for contaminants such as DEG and EG, for example not more than 0.10% volume in volume (v/v). Where the sample does not meet the specification, the consignment (batch) of excipient should be rejected and not used.
對每批或每個批次所列輔料的每一容器進行采樣,并對甲醇或DEG和EG等污染物進行身份和限量測試。每個樣本應符合預定義的規格,包括對DEG和EG等污染物的安全限量,例如不超過0.10%(體積比)。若樣本不符合規格,則應拒收該輔料批次并不得使用。
來源：Internet
